Coronary artery disease (CAD) is the leading cause of mortality worldwide. Annually, CAD imposes significant financial burdens and casualties on healthcare systems across the world. Therefore, the current focus of many health policy making authorities is to find effective ways for the optimal prevention and management of CAD.
Among the most important modifiable risk factors for CAD is dyslipidemia, which is characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), and diminished concentrations of high-density lipoprotein cholesterol (HDL-C). Extensive evidence, including findings of the several landmark trials, has confirmed the beneficial impact of LDL reduction in both primary and secondary prevention of cardiovascular disorders.
According to recent guidelines, optimal levels for serum LDL-C have been suggested to be around 60-70 mg/dL. However, statin—as the most potent LDL-lowering class of drugs—is only able to reduce serum LDL in around 30-50% of cases. Additionally, such a reduction would be achieved with aggressive therapy, which may itself predispose the patient to adverse events, such as myopathies and hepatotoxicity. In recent decades, there has been an increasing focus on boosting HDL concentrations to fulfill the residual cardiovascular risk, which is not compensated by LDL reduction. In addition to their inadequate potency for decreasing serum LDL to the optimal level, statins also have a limited effect on serum HDL-C concentrations.
As is known in the art, liposomes are artificial phospholipid bilayers, which have long been used as carriers to enhance the potency and reduce the toxicity of drugs. These constructs have generated great interest for biomedical purposes due to their biocompatibility, biodegradability, safety and lack of immunogenicity. Nanoliposomes are known to have a short half-life in the circulation. Biodistribution studies have shown that within a few hours of intravenous injection, nanoliposomes are efficiently taken up by hepatic tissue. This uptake has been shown to be performed through receptor mediated endocytosis, a process which normally occurs for the clearance of LDL from circulation.
On the other hand, there is also evidence indicating the coalescence of liposomes containing 75-100% mol anionic phospholipids with LDL, and the uptake of resulting complex via either LDL receptors or macrophages. In addition, liposomes have been shown to undergo vast lipid exchange with plasma lipoproteins, and through these interactions, promote reverse cholesterol transport from peripheral tissues to liver. In spite of these promising mechanisms, the potential of liposomes as anti-dyslipidemic agents has not been well clarified.
Apo lipoprotein B is a large glycoprotein that serves an indispensable role in the assembly and secretion of lipids, and in the transport and receptor-mediated uptake and delivery of distinct classes of lipoproteins. The importance of Apo lipoprotein B spans a variety of functions, from the absorption and processing of dietary lipids to the regulation of circulating lipoprotein levels.
ApoB-100 is the major protein component of LDL and contains the domain required for interaction of this lipoprotein species with the LDL receptor. Therefore, the targeting of liposomes against Apo B-100 is expected to enhance the effects of liposomal formulations on the LDL fraction, and result in greater reduction rates.
The general use of liposomes for the reduction of LDL is known. However, the prior art known to Applicant fails to disclose that the antibody anti-apoB100 can be used in combination with nano liposomes. This particular aspect is absent in the prior art.
The present invention found that the effect of nanoliposomes with different phospholipid composition, Tm and charge on serum levels of lipoproteins. In connection with the present invention, a study was also undertaken to evaluate the impact of targeting liposomes to LDL via coupling to apolipoprotein B-100 (apo B-100) monoclonal antibodies. A proper anionic-to-neutral phospholipid ratio for preparing the said liposomal composition is set forth herein. The objects and features of the present invention, will become apparent in the detailed description of the invention set forth below.
There is, therefore, a present need for such efficacious treatments for coronary artery diseases, as well as related treatments concerning ameliorating the negative effects of bad LDL and other cholesterol levels.
These and many other objects are met in various embodiments of the present invention, offering significant advantages over the known prior art and consequent benefits to all mankind.